PB2524: TRIAL IN PROGRESS: THE HIBISCUS-KIDS STUDY, A SINGLE-ARM, OPEN-LABEL, PHASE 1/2 STUDY TO EVALUATE THE PHARMACOKINETICS AND SAFETY OF ETAVOPIVAT IN PEDIATRIC PATIENTS WITH SICKLE CELL DISEASE
Authors: Raffaella Colombatti, Julie Kanter, Eric Wu, Leila J. Clay, Andrew Campbell
Journal: HemaSphere (2023)

Topic: 26. Sickle cell disease Background: In sickle cell disease (SCD), a single β-globin gene mutation causes sickle hemoglobin (HbS) to polymerize and red blood cells (RBCs) to aggregate, leading to hemolytic anemia and vaso-occlusive events. These events generally present as a vaso-occlusive crisis (VOC), an acute episode of pain. With symptom onset in infancy, patients experience more and more VOCs, long-term organ damage, and systemic co-morbidity occurrences through the years, resulting in a shortened lifespan. Therefore, novel, safe therapies are urgently needed for children with SCD to prevent organ damage and cumulative co-morbidity from early life on. Etavopivat is a once-daily, selective erythrocyte pyruvate kinase (PKR) activator in clinical development to treat patients with SCD and other hemoglobinopathies. The hypothesis is that PKR activation will reduce HbS polymerization and improve RBC membrane function via decreasing 2,3-diphosphoglycerate (DPG) and increasing adenosine triphosphate (ATP). This will lead to a decrease in RBC sickling and hemolysis and hence reduce the cause of vascular obstruction and anemia (Schroeder et al., J Pharm Exp Ther 2022; Telen et al., HemaSphere 2022). Aims: Our aim is to describe the design of the HIBISCUS-KIDS study (PACTR202209604592389), a single-arm, open-label, phase 1/2 trial to evaluate the pharmacokinetic (PK) response, safety, and tolerability of etavopivat in pediatric patients with SCD. Methods: Patients will receive a 400 mg etavopivat dose daily for a 24-week primary treatment period followed by a 72-week extension period (Figure). For this study, up to 50 patients aged 12 to under 18 years will be enrolled at 15 sites in 6 countries (Canada, UK, Lebanon, Turkey, Nigeria, and Kenya). After a minimum of 12 weeks, data on safety, PK, and clinical activity will be evaluated by the sponsor and shared with the safety review committee to inform further decisions on a potential inclusion of patients younger than 12 years. Inclusion criteria are a confirmed diagnosis of SCD with a documented genotype and a hemoglobin value from 5.5 to below 10.5 g/dL. Key exclusion criteria are hospitalization, hospital or clinic visit for more than 10 VOCs within the 12 months before treatment start, or hospitalization for any SCD-related complication within 14 days of the screening period. The primary objective is to assess etavopivat PK based on the primary endpoints: maximum concentration, area under the concentration time curve, and steady state etavopivat plasma exposure in children with SCD. Safety and tolerability of etavopivat during the 24-week primary treatment period is a co-primary endpoint and will be analyzed based on number of reported adverse events (AEs), severe AEs, and AEs related to etavopivat, premature discontinuations, dose interruptions, and dose reductions of etavopivat. Key secondary and exploratory study objectives are to assess the effects of etavopivat on Hb response, VOC occurrences, changes in fatigue and cerebral blood flow, silent cerebral infarct incidences, and functional capacity. Results: This study is in progress and results are yet to be available. First dose, first patient was achieved in Lebanon, and sites within Canada, UK, Turkey, Nigeria, and Kenya are planned to open for enrolment. Summary/Conclusion: Etavopivat is a novel, investigational, selective PKR activator with the potential to improve RBC health and lifespan. This Phase 1/2 study will assess the safety and tolerability of etavopivat in children with SCD and add additional pediatric data along the phase 2/3 HIBISCUS trial (NCT04624659) in adults and adolescents with SCD.Keywords: Clinical trial, Pediatric, Pharmacokinetic, Sickle cell disease